Metastatic breast cancer is an incurable disease, accounting for about 20 percent of cancer mortality in women. Despite the use of surgery, radiation, hormone therapy, and chemotherapy for controlling metastatic spread, 44,000 women each year fail these modalities. Combining immunotherapy with chemotherapy may provide additional therapeutic options. The use of paracrine cytokine tumor vaccines is a novel approach for activating antitumor immunity, and can cure mice with low tumor burdens. Our phase I trial of an allogeneic tumor vaccine genetically modified to secrete GM-CSF in patients with surgically resected pancreatic cancer showed that the vaccine was well-tolerated, and appeared to provoke dose-dependent immune activation and prolongation of disease-free survival. Several groups have observed that some chemotherapeutic agents can by themselves modulate immune responses. We recently found that Cyclophosphamide (Cy) given one day before with Doxorubicin (Dox) given 7 days after vaccination can induce antitumor immunity potent enough to cure HER-2/neu transgenic mice of pre-existing tumors. These mice demonstrate tolerance to HER-2/neu that is similar to mechanisms of tumor tolerance in patients with cancer. This proposed phase I trial will test the hypothesis that an allogeneic GM-CSF secreting breast tumor vaccine given in sequence with Cy and Dox can generate tumor-specific immunity in patients with metastatic breast cancer. Trial endpoints will include: 1) safety, 2) induction of antitumor immune responses against HER-2/neu as a surrogate target including measurements of antibody titers, delayed type hypersensitivity against HER-2/neu peptides, and in vitro T cell activity, 3) clinical responses. In addition, in vitro T cell lines will be developed using lymphocyte and tumor specimens obtained from patients following vaccination and used to identify and characterize additional antigens against which the immune response is generated. Twenty-seven patients with stage IV breast cancer who have undergone 0-2 previous therapies will be enrolled. A novel multifactorial study design (adapted from Plackett and Burman methods) will be used to identify optimal doses of Cy and Dox that enhance the vaccine induced antitumor responses. If successful, this trial will also spur the development of tumor vaccines for early stage disease. In addition, characterization of breast tumor antigens may lead to the development of recombinant vaccines that can more efficiently activate antitumor immunity.